Activation of Striatal Dopamine Receptors by Psychostimulants: Chemical Anatomy, Autonomic and Behavioural Effects
Vol. 52, No. 3, Aug, 2005 Danish Medical Bulletin

Author E-mail : pedro@pet.auh.dk
Author(s) : Pedro Rosa Neto
Author Address : Building 10, Aarhus University Hospital, Noerrebrogade 44, 8000 Aarhus C, Denmark.
Keyword(s) : Psychostimulants;Striatal Dopamine;Behavioural Effects;Anatomy;Dopamine Receptors;Radioligands;D-amphetamine;Butyrophenones
Abstract

Pharmacological activation of dopamine neurotransmission can be
assessed by Positron Emission Tomography (PET) studies of changes in the binding
of radioligands for dopamine D 2 receptors. The present
thesis focuses on the use of this activation method to study receptor mapping,
receptor pharmacology and behavioural aspects related to perturbation of
dopamine neurotransmission in humans and animal models.


This thesis first describes the use of
PET to map the distributions of dopamine D 2/3 and D 1 receptors in pigs and in monkeys, frequently used models for
dopamine activation studies. As in humans, pigs and monkeys had a negative
rostro-caudal gradient in the t -maps calculated from
the statistical contrast between the normalized binding maps for D 1 and D 2/3 receptors. A positive
rostro-caudal gradient for D 2/3 binding was observed
only in monkeys. These results suggest a relative predominance of D 1 over D 2/3 receptors in the limbic
striatum in mammals. In monkeys, D 2/3 receptors were
more predominant in the motor striatum; the apparent lack of gradients in 11 C-raclopride binding in pig striatum might be attributed to
their less sophisticated associative and motor circuits as compared to primates.

The effects of the psychostimulant
3,4-methylenedioxy-methamphetamine (MDMA, "Ecstasy") on cerebral blood flow
(CBF) and dopamine receptor availability were tested. Unlike most previous
studies of d-amphetamine, MDMA evoked a progressive decline of butyrophenone
( 11 C-NMSP) binding. MDMA-evoked hyperthermia correlated
with increased CBF brain structures linked to central regulation of body
temperature. These results suggest that the co-release of dopamine and serotonin
by MDMA may influence the patterns of binding changes in living striatum.

ADHD is a highly prevalent pediatric
neuropsychiatric disorder which is presently treated with psychostimulants. The
effects of methylphenidate (0.3 mg/kg, p.o.) on the binding of 11 C-raclopride was measured by PET in
nine young ADHD patients. There was a negative correlation between the magnitude
of methylphenidate-evoked decline in 11 C-raclopride
binding and the severity of inattention and impulsivity, measured by a
continuous performance test. Thus, the dopamine activation paradigm was
successfully used as a tool to link behavioural disturbance with reduced
dopamine neurotransmission in patients with ADHD.

Together, these findings highlight PET
as a method for linking behavioural, autonomic and pharmacological aspects of
dopaminergic activation with segregated striatal circuits. (more at Psych Central...)